Newborn Screening for Severe Combined Immunodeficiency

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Key points

  • The T-cell receptor excision circle (TREC) assay is an effective screening tool for severe combined immunodeficiency (SCID).

  • The TREC assay was designed to detect typical SCID and leaky SCID, but any condition causing low naïve T-cell counts will also be detected.

  • Newborn screening for SCID using the TREC assay has proven itself to be highly sensitive and cost-efficient. This review covers the history of SCID newborn screening, elaborates on the SCID subtypes and TREC assay limitations, and

History of severe combined immunodeficiency newborn screening

In the United States, NBS programs run at the state level began in the 1960s with the development of a filter paper–based system, onto which newborns’ heel-stick blood samples were spotted and dried. Robert Guthrie’s innovation, spurred by his experience with his son and niece experiencing neurodevelopmental delays from phenylketonuria (PKU), provided blood samples that were easy to obtain and stable. His assay for PKU was accurate, consistent, and inexpensive, providing the paradigm for future

The T-cell receptor excision circle assay for severe combined immunodeficiency

T lymphocytes’ ability to provide adequate defense against a diverse repertoire of pathogens requires an equally diverse range of T-cell receptors (TCR). Recombination of a large number of gene loci organized into segments, known as variable (V), diversity (D), and joining (J) regions. These genes code for TCR chains (and antibody molecules) and lie near genes coding for constant regions. During TCR rearrangement, a series of enzymes introduce double-stranded DNA breaks at specific sites,

Severe combined immunodeficiency subtypes and other conditions detected by T-cell receptor excision circles assay

The TRECs assay was designed to detect typical SCID and leaky SCID, but any condition causing low naïve T-cell counts will also be detected. Typical SCID is diagnosed when there are less than 300 T cells/μL and less than 10% of normal T-cell proliferation on phytohemagglutinin mitogen proliferation culture.24 Frequently, these patients will also exhibit maternal T-cell engraftment owing to survival of maternal T cells that have crossed transplacentally. These cells would normally be eliminated

Results of severe combined immunodeficiency newborn screening

Kwan and colleagues30 published the early results of SCID NBS for more than 3 million infants (n = 3,030,083) from programs in the first 10 states to offer screening, and the Navajo nation. The states included were California, Colorado, Connecticut, Delaware, Massachusetts, Michigan, Mississippi, New York, Texas, and Wisconsin. All programs used the TRECs assay to screen newborns; positive assays were confirmed with flow cytometry to definitively determine T-, B-, and NK-lymphocyte numbers, and

Evaluation of infants with positive T-cell receptor excision circles results

The protocol for evaluating infants with positive (low) TREC results on NBS varies by state.31 Results are not considered abnormal if numbers of both TRECs and β-actin are found to be low, because this would indicate degradation of the DNA sample as opposed to true T-cell lymphopenia. Some states have protocols that will repeat the TREC assay on premature infants, which are known to more frequently have low TRECs despite no intrinsic defect in T-cell production, until these infants reach a

Summary

The TRECs assay is an effective screening tool for SCID. TREC numbers are an indication of naïve T cells, which have recently migrated from the thymus. It follows that the TREC assay detects T-cell lymphopenia from any cause. Most infants with positive TRECs assays do not have SCID (approximately 90%, according to 1 study).30 Congenital syndromes and secondary causes of T-cell lymphopenia are the most common cause of low TREC numbers on NBS. Complete or severe DiGeorge syndrome is the most

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    Disclosure Statement: The authors have nothing to disclose.

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